Processes for producing pyridoindole derivatives

ABSTRACT

A process for producing pyridiondole derivatives represented by general formula (III) or their salts (wherein R 1  represents hydrogen, lower alkyl or lower alkenyl; R 2  represents hydrogen, lower alkyl or halogeno; and R 3  represents optionally substituted imidazolyl), which comprises reacting a compound represented by general formula (I) or its salt (wherein R 1  and R 2  are each as defined above) with a compound represented by general formula (II) or its salt (wherein R 3   a  represents optionally substituted imidazolyl having an imino protecting group; and X represents halogeno), followed by a reaction for eliminating the imino protecting group); and a process for producing optically active pyridoindole derivatives represented by general formula (IV) or their salts: which comprises reacting a racemic mixture of the pyridoindole derivative represent by formula (III) or its salt with (1R)-(-)-10-camphorsulfonic acid.

CROSS REFERENCE

This application is a 371 of PCT/JP96/02692 filed Sep. 18, 1996.

TECHNICAL FIELD

This invention relates to processes for the preparation of pyridoindolederivatives and salts thereof which are pharmaceutically effective as a5-hydroxytryptamine (5-HT) antagonism.

BACKGROUND ART

Some pyridoindole derivatives indicated by the following general formula(III) and salts thereof are publicly known in the Japanese Kokai TokkyoKoho 2-117675. These pyridoindole derivatives and salts thereof possessa 5-HT antagonism and are effective in the treatment and the preventionof central nervous system (CNS) disorders such as psychosis (e.g.,schizophrenia, mania, etc.), anxiety, depression and so forth; painssuch as headaches (e.g., migraine headaches, cluster headaches, vascularheadaches, etc.), neuralgia (e.g., trigeminal neuralgia, etc.) and soforth; gastrointestinal disorders such as symptoms of gastrointestinaldysfunction accompanying dyspepsia, peptic ulcer, reflux esophagitis,meteorism, and the like, irritable bowel syndrome (IBS), and the like;nausea or vomiting accompanying cancer treatment; motion sickness; andso forth. ##STR1## wherein R¹ is hydrogen, a lower alkyl group or alower alkenyl group, R² is hydrogen, a lower alkyl group or a halogen,and R³ is an imidazolyl group which may have a suitable substituent (s).

A process for the synthesis of(±)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(IIIa) is described in Japanese Kokai Tokkyo Koho 2-117675 through thefollowing 5 steps which are illustrated below specifically as an exampleof the process for the synthesis of pyridoindole derivatives (IIIa).

Conventional Route: ##STR2##

In the above described conventional processes, the object compound(IIIa) is obtained from the compound (Ia) by means of processes throughfive steps, which comprises an alkylation first being carried outthrough an aldol reaction with an aldehyde (V), followed by acetylation,deacetoxification, detosylation, and reduction to synthesize thecompound (IIIa). Here, the yield from the compound (Ia) to the objectcompound (IIIa) is 68%. The processes for producing the pyridoindolederivatives shown by the general formula (III) which are disclosed inthe aforesaid Japanese Tokkyo Koho have drawbacks in the complicatedprocesses due to the large number of steps, in the low yield, and in thehigher cost, and so forth.

Furthermore, the aforesaid pyridoindole derivative is generally obtainedas a racemic mixture. Moreover, the stereoisomers of said pyridoindolederivatives are generally obtained by the resolution process involving areaction with an optically active reagent such as, for example,diparatoluoyltartaric acid or the like. However, the conventionaloptical resolution processes using diparatoluoyltartaric acid or thelike have the drawback not only in the low yield but also in the use ofa large amount of the solvent for the crystallization, and also areinavoidable to use chloroform which is in trouble for its safety.

DISCLOSURE OF INVENTION

The present invention provides a process for producing a pyridoindolederivative (III) or a salt thereof in one single step illustrated in theProcess 1, shown below; which comprises a direct alkylation of acompound (I) or a salt thereof with an alkylating agent (II) or a saltthereof. This process is superior in it's simplicity and it's yield tothe process disclosed in the aforesaid Japanese Kokai Tokkyo Koho.##STR3## wherein R¹ is hydrogen, a lower alkyl group or a lower alkenylgroup, R² is hydrogen, a lower alkyl group or a halogen, R³ _(a) is animidazolyl group substituted with an imino protective group, which mayhave a suitable substituent (s), R³ is an imidazolyl group which mayhave a suitable substituent (s), and X is a halogen.

In addition, the present invention also provides a process for producingan optically active pyridoindole derivative (IV) or a salt thereof froma racemic mixture of the pyridoindole derivative (III) or a salt thereofby means of the following process, which is superior to the process inthe aforesaid Japanese Kokai Tokkyo Koho at the point of it's yield andit's safety due to the unuse of harmful chloroform and so on. ##STR4##

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1to 4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" may include a straight or branched one having 1to 6 carbon atom (s) such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, benzyl, hexyl, preferably the one having 1 to4 carbon atoms, and the like, in which the most preferred one is methyl,ethyl, or propyl.

Suitable "lower alkenyl" may include vinyl, 1-propenyl, allyl,1-butenyl, 2-butenyl, 2-pentenyl, preferably the one having 2 to 4carbon atoms, and the like, in which the most preferred one is allyl.

Suitable "halogen" may include fluorine, chlorine, bromine and iodine.

Suitable "imidazolyl" may include 1H-imidazol-1-yl, 1H-imidazol-2-yl,1H-imidazol-4-yl and 1H-imidazol-5-yl.

Suitable "substituent (s)" in the term "imidazolyl which may have asuitable substituent (s)" and "imidazolyl substituted with an iminoprotective group, which may have a suitable substituent (s)" may includeany group conventionally used in pharmacological fields such as theaforementioned lower alkyl or the like.

Suitable "imino protective group" may include a conventional one, inwhich the preferable example is acyl [e.g. N,N-di (lower) alkylsulfamoylgroups (e.g., N,N-dimethylsulfamoyl group, etc.), lower alkanesulfonylgroups (e.g., mesyl group, etc.), arenesulfonyl groups (e.g., tosylgroup, etc.),etc], and the like wherein, a tosyl group(p-toluenesulfonyl group) is most preferable.

It is described below in detail that the process for producingpyridoindole derivative (III) or a salt thereof, and the process for theproducing an optically active pyridoindole derivative (IV) or a saltthereof from a racemic mixture of a pyridoindole derivative (III) or asalt thereof, of the present invention.

Process 1

A compound (I) or a salt thereof is reacted with a base to form anenolate, the enolate is subjected to an alkylation reaction by using analkylating agent (II) or a salt thereof, and thus obtained alkylatedcompound is subjected, without an isolation, to a removal reaction ofthe imino protective group, to obtain a pyridoindole derivative (III) ora salt thereof.

An appropriate base for use to form an enolate from the compound (I) ora salt thereof prior to the alkylation reaction, may include inorganicand organic bases such as, for example, alkali metals (e.g., lithium,sodium, potassium, etc.), alkaline earth metals (e.g., magnesium,calcium, etc.), alkali metal alkoxides (e.g., sodium methoxide, sodiumethoxide, potassium t-butoxide, etc.), alkali metal hexamethyldisilazit,and so forth.

In this alkylation reaction, the selection of the imino protective groupand the halogen (X group) of the alkylating agent (II) or a salt thereofare important, since these influence the stability of the alkylatingagent (II) or a salt thereof and the progress of the alkylationreaction.

From the perspective of stability of the alkylating agent (II) or saltthereof, the use of a tosyl group (p-toluenesulfonyl group) as the iminoprotective group and the use of chlorine as the halogen (X group) aremost preferable.

When a tosyl group (p-toluenesulfonyl group) as the imino protectivegroup and chlorine as the halogen (X group) in the alkylating agent (II)or a salt thereof are each used, the progress of the alkylation reactionis facilitated by the addition of sodium iodide to this alkylating agentin the presence of a suitable solvent while agitation at approximately20° C., since the chlorate is converted into an iodate (halogenexchange).

The alkylation reaction is normally carried out in a conventionalsolvent, such as dioxane, tetrahydrofuran, diethyl ether, diisopropylether, chloroform, methylene chloride, ethylene chloride,N,N-dimethylformamide or any other desired organic solvent which doesnot exert an adverse effect on the reaction.

When the base used is in the form of a liquid, this may also serve asthe solvent.

While there is no particular limitation with regard to reactiontemperature, cooling is normally performed while the reaction is beingcarried out.

Following the alkylation reaction, by subjecting the alkylate obtainedtherefrom, without isolation to a removal reaction of an iminoprotective group to give a racemic mixture of pyridoindole derivative(III) or a salt thereof with the satisfactory yield.

As appropriate processes for removing the imino protective group, anyconventional processes which are used for the removal of an iminoprotective group from an imidazolyl group, such as, hydrolysis,reduction, and so forth, may be exemplified.

With respect to a reduction, a chemical reduction by using an alkalimetal borohydrides (e.g., sodium borohydride, etc.), a catalyticreduction by using a palladium catalysts (e.g., palladium--carbon,etc.), and the like may be exemplified With respect to a hydrolysis,this is preferably carried out in the presence of an acid or a base.

A suitable base may include, for example, inorganic bases such as alkalimetal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.),alkaline earth metal hydroxides (e.g., magnesium hydroxide, calciumhydroxide, etc.), alkali metal carbonates (e.g., sodium carbonate,potassium carbonate, etc.), alkaline earth metal carbonates (e.g.,magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates(e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metalacetates (e.g., sodium acetate, potassium acetate, etc.), alkaline earthmetal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.),alkali metal hydrogenphosphates (e.g., disodium hydrogenphosphate,dipotassium hydrogenphosphate, etc.) and the like, and organic basessuch as 1,5-diazabicyclo[4.3.0]nonan-5-one,1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[5.4.0]undecene-5 and thelike. The hydrolysis using a base is preferably carried out in water, ina hydrophilic organic solvent, or in a mixture thereof.

A suitable acid may include organic acids (e.g., formic acid, aceticacid, propionic acid, etc.) and inorganic acids (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

This hydrolysis is preferably carried out in an organic solvent, inwater, or in the mixture solvent thereof.

The reaction temperature is not critical, the reaction can be normallycarried out under cooling, at the room temperature, or under heating.

The reaction scheme of the process for producing(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(IIa) is illustrated below.

Synthetic Route for Compound (IIIa) of the Present Invention: ##STR5##

This invention provides a compound (IIIa) in high yield (88%) by usingfirstly a process for the synthesis of the alkylating agent (IIa), whichhad not been synthesized conventionally due to the problems with thestability, and secondly a direct alkylation of the compound (Ia). Morespecifically, this invention provides an improvement of reactivity ofthe compound (IIa) by using a halogen exchange reaction of thealkylating agent (IIa) with sodium iodide.

Process 2

A (±)isomer pyridoindole derivative (III) or a salt thereof is reactedwith (1R)-(-)-10-camphorsulfonic acid (hereinafter referred to as(R)·CSA) to obtain a (+)isomer pyridoindole derivative·CSA salt and a(-)isomer pyridoindole derivative·CSA salt. The (+)isomer pyridoindolederivative·CSA salt and the (-)isomer pyridoindole derivative·CSA saltare resolved using their different solubilities in a solvent. As thesolvent, one may use, for example, hydrous ethanol or the like. Theoptically active (+)isomer pyridoindole derivative (IV) can be obtainedby desalting is the resolved (+)isomer pyridoindole derivative·CSA salt.Desalting is carried out in the presence of a base, e.g. sodiumhydroxide. The resolved (+)isomer pyridoindole derivative·CSA salt ispurified by recrystallization or the like prior to desalting. Inaddition, (+)isomer pyridoindole derivative yield is increased byracemizing the resolved (-)isomer pyridoindole derivative·CSA salt bymeans of a process in conventional use, e.g. a process indicated in theExamples described below, and again carrying out optical resolution.

The (+)isomer pyridoindole derivative (IV) may be converted to asuitable salt by means of a process in conventional way, e.g. a processindicated in the Examples described below. A suitable salt may includeconventional nontoxic pharmaceutically acceptable salts; to wit a baseor an acid addition salt. More specifically, they may include the saltsof inorganic bases such as alkali metal salts (e.g., sodium salts,potassium salts, cesium salts, etc.), alkaline earth metal salts (e.g.,calcium salts, magnesium salts, etc.), and ammonium salts; salts oforganic bases such as organic amine salts (e.g., triethylamine salts,pyridine salts, picoline salts, ethanolamine salts, triethanolaminesalts, dicyclohexylamine salts, N,N-dibenzylethylenediamine salts,etc.); salts of inorganic acids (e.g., hydrochloride, hydrobromide,sulfate, phosphate, etc.); organic carboxylate and organic sulfonates(e.g., formate, acetate, trifluoroacetate, maleate, tartrate,methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); salts ofbasic amino acids and acidic amino acids (e.g., arginine, aspartic acid,glutamic acid, etc.); and so forth.

An appropriate salts of the object compound and the starting compound inProcess 1 and Process 2 can be referred to the ones as mentioned above.

Below, we describe the present invention in further detail withreference to Preparations and Examples.

PREPARATION 1

4-chloromethyl-5-methyl-imidazole hydrochloride (100 g) was suspended indimethylacetamide (400 ml), and p-toluenesulfonyl chloride (102.7 g) wasadded thereto while cooling over ice bath. N-methylmorpholine (151.4 g)was dropped therein under the interior temperature of 0-10° C. Aftercompletion of the adding, agitation at the same temperature for anadditional 30 minutes was continued. After the reaction is completed,ethyl acetate (1,000 ml) and water (500 ml) were added to the reactionsolution and the crystals were thoroughly dissolved, and thereafterliquid fractions were separated. The water layer was extracted withethyl acetate (300 ml). Ethyl acetate fractions were combined, and werewashed twice, with 10% aqueous citric acid (300 ml) and 20% brine (1,000ml). The solution was dried with anhydrous magnesium sulfate, and thenthe solvent was removed under vacuum. To the residue, n-heptane (500 ml)was added, cooled over ice bath, and then precipitated crystals werecollected by filtration. They were dried overnight under vacuum toobtain the mixture of 1-tosyl-4-chloromethyl-5-methyl-imidazole and3-tosyl-4-chloromethyl-5-methyl-imidazole as white crystals (134.7 g).

1-Tosyl-4-chloromethyl-5-methyl-imidazole NMR (CDCl₃, δ): 2.28 (3H, s),2.46 (3H, s), 4.46 (2H, s), 7.38 (2H, d), 7.78 (2H, d), 8.09 (1H, s)

3-Tosyl-4-chloromethyl-5-methyl-imidazole NMR (CDCl₃, δ): 2.21 (3H, s),2.44 (3H, s), 4.80 (2H, s), 7.36 (2H, d), 7.85 (2H, d), 8.07 (1H, s)

EXAMPLE 1

Under nitrogen stream, sodium iodide (97.8 g) and a mixture of1-tosyl-4-chloromethyl-5-methyl-imidazole and3-tosyl-4-chloromethyl-5-methyl-imidazole (186 g) in tetrahydrofuran(1,000 ml) were agitated vigorously at an interior temperature of 18˜23°C. for 2 hours, and after carrying out halogen exchange, the reactionsolution was cooled to an interior temperature of -40˜-50° C. In aseparate reaction vessel, under nitrogen stream,8,9-dihydro-10-methyl-pyrido[1,2-a]indol-6(7H)-on (100 g) was dissolvedin tetrahydrofuran (900 ml), cooled to -40˜-50° C. and a 1.35 N solutionof lithium hexamethyldisilazit/tetrahydrofuran-n-hexane (409 ml) weredripped therein while maintaining at same temperature. After drippingwas completed, the reaction was carried out under the agitate at sametemperature for an additional 30 minutes and thereafter the solution wasdripped into the halogen exchange reaction solution prepared above whilemaintaining a temperature of -40˜-50° C. The reaction was carried out atthe same temperature for 15 minutes, and acetic acid (12.1 g) was addedthereto. An interior temperature was raised to 5˜10° C., then 5% aqueoussodium thiosulfate (1,000 ml) was added thereto, and the upper layer wascollected. It was concentrated under vacuum until the volume isapproximately 800 ml. After the concentrating is completed, the mixtureof methanol (400 ml), water (200 ml), and concentrated hydrochloric acid(100 ml) was added thereto, and were agitated for 3 hours after theinterior temperature was raised to 48˜53° C. After the reaction iscompleted, the solution was adjusted to pH 7.8-8.2 with 12% aqueoussodium hydroxide solution, and was concentrated under vacuum untilvolume is approximately 800 ml. Ethyl acetate (300 ml) was addedthereto, adjusted to pH 10.5±0.2 with 12% aqueous sodium hydroxide,thereafter was cooled to a temperature of not higher than 10° C., andthe precipitated crystals were collected by filtration. They were washedwith ethyl acetate (300 ml) and water (500 ml), and then dried overnightunder vacuum to obtain(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-oneas yellowish-brown crystals (129.0 g).

NMR (CDCl₃, δ): 1.83-1.97 (1H, m), 2.15 (3H, 1H, d+m), 2.22 (3H, d),2.79-3.14 (5H, m), 7.3 (2H, m), 7.3-7.4 (2H, m+s), 8.45 (1H, m)

EXAMPLE 2

(1) The mixture of(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(50 g) and (1R)-(-)-10-camphorsulfonic acid (CSA) (42.7 g) weredissolved 5% hydrous ethanol (250 ml) under reflux. After cooling, atthe interior temperature of 33° C. the seed crystals (0.1 g) were addedthereto, and the agitate at 20˜30° C. for 20 hr caused to thoroughlyprecipitate(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt and(-)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt. 5% hydrous ethanol (100 ml) was added thereto and the mixture wasagitated at the same temperature for 1 hr, 5% hydrous ethanol (50 ml)was added thereto and the mixture was agitated for 1 hr, 5% hydrousethanol (100 ml) was added thereto and the mixture was agitated for 1hr, and 5% hydrous ethanol (50 ml) was added thereto and the mixture wasagitated for 1 hr, and(-)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt were redissolved. The solution was allowed to stand overnight,thereafter the crystals were collected by filtration, washed with 50 mlof ethanol, and thereafter dried overnight under vacuum to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt as white coarse crystals.

Yield=22.7 g. Percent yield 25.3%.

(+)isomer CSA salt: (-)isomer CSA salt=96.0:4.0 (here and below, LCmeasurement values as determined by the liquid chromatographic processdescribed below).

(2) Purification

(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6 (7H)-one·CSA salt (22.0 g)obtained above was dissolved in ethanol (110 ml) under reflux. Aftercooling, it was agitated for 3 hr at an interior temperature of 20˜30°C., thereafter the precipitated crystals were collected by filtrationand washed with ethanol (22 ml). They were dried overnight under vacuumto obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt as white crystals.

Yield=19.9 g. Percent yield=90.5%.

Isomer ratio: (+)isomer CSA salt: (-)isomer CSA salt=99.7:0.3 (LCmeasurement values).

(3) The mother liquor and the washings were combined, water (500 ml) wasadded thereto, and were adjusted to pH8.9 with 8% aqueous sodiumhydroxide (approx. 50 ml) at an interior temperature of 20˜30° C. Afteragitating for 1 hr, the precipitated crystals were collected byfiltration, washed with water (150 ml), and thereafter were driedovernight under vacuum to recover(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-oneas light yellow crystals.

Yield=34.8 g. Percent yield=69.5%.

Isomer ratio: (+)isomer: (-)isomer=34.3:65.7 (LC measurement values).

(4) Re-racemization

(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(30.0 g) [isomer ratio: (+):(-)=34.3:65.7] obtained above was suspendedin toluene (300 ml), and 1,8-diazabicycloundecene (DBU) (15.7 g) wasadded thereto, and was refluxed for 10 hr. It was cooled to an interiortemperature of 20˜30° C., and the crystals were collected by filtration,washed with toluene (30 ml), and thereafter were dried overnight undervacuum and re-racemized to obtain(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one.

Yield=27.4 g. Percent yield=91.2%. Isomer ratio: (+)isomer: (-)isomer48.1:51.9 (LC measurement values).

(5) According to a similar manner to that of Example 2-(1),(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt was obtained by using(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(20.0 g).

Yield=8.00 g. Percent yield=22.5%.

Isomer ratio: (+)isomer CSA salt: (-)isomer CSA salt=95.6:4.4 (LCmeasurement values).

(6) Purification

According to a similar manner to that of Example 2-(2),(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt (7.00 g) obtained according to the manner of Example 2-(5), wasrecrystallized with ethanol and purified to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt.

Yield=6.33 g. Percent yield=90.4%.

Isomer ratio: (+)isomer CSA salt: (-)isomer CSA salt=99.7:0.3 (LCmeasurement values).

(7)(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt (15.0 g) was suspended in methanol (45 ml) and water (105 ml), andadjusted to pH10.6 with 8% aqueous sodium hydroxide (10 ml) at aninterior temperature of 20˜30° C. It was agitated for 1 hr at the sametemperature, thereafter the crystals were collected by filtration,washed with water (45 ml), and thereafter dried overnight under vacuumto obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one.

Yield=8.59 g. Percent yeild=102.6%.

(8)(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(8.0 g) was dissolved in ethanol (80 ml) and water (72 ml), and 6 Nhydrochloric acid (8 ml) was added thereto at an interior temperature of20˜30° C., and it was agitated at the same temperature for 1 hr. It wasclarified by filtration, and the container and so forth was washed withethanol (8 ml). Water (272 ml) was dripped therein at a temperature of20˜30° C. over the course of 20 min, and the seed crystals (0.016 g)were added thereto, and it was agitated at the same temperature for 3hr, cooled to 0˜5° C., and agitated for 3 hr. The precipitated crystalswere collected by filtration, washed with water (32 ml), and thereafterdried overnight under vacuum to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·hydrochloride.

Yield=7.38 g. Percent yield=82.0%.

Optical Resolution Liquid Chromatographic LC Conditions

Column: CHIRAL-AGP (mfd. by Chromtech, Sweden)

Internal diameter 4 mm, length 100 mm, bead diameter 5 micron

Column temperature: 35° C.

Mobile phase: 30% hydrous acetonitrile, pH 7

Na₂ HPO₄. 12H₂ O: 2 g

KH2PO4: 0.5 g

Distilled water: 700 ml

Acetonitrile: 300 ml

Flow rate: 0.8 ml/mm; Detection wavelength: 254 nm (+)isomer: Approx.2.5 min; (-)isomer: Approx. 4 min

EXAMPLE 3

(1)(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(100 g), (1R)-(-)-10-camphorsulfonic acid monohydrate (85.3 g), andradiolite (1 g) in ethanol (1,000 ml) were heated under reflux. It wascooled to 35° C., and 0.2 g of seed crystals were added thereto,thereafter it was agitated at an interior temperature of 20˜30° C. for 3hr, and after ethanol (1,000 ml) was added therto, it was agitatedovernight at 20˜30° C. The following day, water (25 ml) was addedthereto and it was agitated for 1 hr at 20˜30° C., and after thetemperature was raised to 33˜37° C., it was agitated for 30 min. It wascooled to 20˜30° C., thereafter the precipitated crystals were collectedby filtration, washed with ethanol (100 ml), and dried overnight undervacuum to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt as colorless coarse crystals.

Yield=53.9 g (including seed crystals+radiolite). Percent yield=28%.

(+)isomer CSA salt: (-)isomer CSA salt=96.0:4.0 (LC measurement values).

NMR (CDCl₃, δ): 0.80 (3H, s), 1.03 (3H, s), 1.8 (lH, m), 1.9-2.2(2H+2H+2H+1H, m), 2.10 (3H, s), 2.32 (3H, s), 2.5-3.1 (2H+2H+1H+1H, m),3.3-3.5 (2H, m), 7.2 (2H, m), 7.4 (1H, m), 8.3 (1H, m), 8.49 (1H, s),13.8 (1H, broad).

(2) Under vacuum, the above mother liquor was concentrated toapproximately 1,000 ml, and 1,000 ml of water was added thereto,thereafter it was adjusted to pH13, and the precipitated crystals werecollected by filtration, and were dried under vacuum to recover(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one.

Yield=73.8 g.

(3) Re-racemization

38.3 g of DBU and 73.8 g of the recovered crystals (73.8 g) obtainedaccording to a manner of Example 3-(2) in toluene (738 ml) were heatedunder reflux for 3 hr. After cooling, the crystals were collected byfiltration at an interior temperature of 20˜30° C., washed with toluene(150 ml) and water (150 ml), and thereafter dried overnight under vacuumto obtain(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-oneas crystals.

Yield=65.3 g.

(+)Isomer CSA salt: (-)isomer CSA salt=49.0:51.0 (LC measurementvalues).

(4) By using(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one(65.3 g) obtained according to a manner of Example 3-(2), according to asimilar manner to that of Example 3-(1),(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt as coarse crystals was obtained.

Yield=35.2 g. Percent yield=18.3% (overall yield from(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one=46.3%).

(+)Isomer CSA salt: (-)isomer CSA salt=96.0:4.0 (LC measurement values).

(5) Purification

The mixture of(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt (53.9 g) obtained according to a manner of Example 3-(1) and(±)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt (35.2 g) obtained according to a manner of Example 3-(4) wasdissolved in ethanol (446 ml) by heating under reflux. The powderedcarbon (1.8 g) was added thereto and refluxed again, thereafter theradiolite and the powdered carbon was collected by filtration while hot.The filtrate was cooled to room temperature, thereafter the precipitatedcrystals were collected by filtration to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt as colorless crystals.

Yield=75.2 g. Percent yield=86%.

(+)Isomer CSA salt: (-)isomer CSA salt=99.6:0.4 (LC measurement values).

(6)(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·CSAsalt (100 g) was suspended in the mixture of methanol (300 ml) anddeionized water (700 ml), and adjusted to pH11.5-12.5 with 24% aqueoussodium hydroxide, the crystals were collected by filtration, washed withwater, and dried to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-oneas white crystals.

Yield=53.6 g. Percent yield=96%.

(7)(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-on(100 g) was suspended in the mixture of ethanol (300 ml) and deionizedwater (300 ml), and 6 N hydrochloric acid (100 ml) was added thereto atan interior temperature of not less than 30° C. After the additionthereof, it was heated to an interior temperature of 65˜75° C. and theprecipitated crystals were dissolved. After the dissolution, it wasclarified by filtration, and the filtration vessel and so forth werewashed with 200 ml of deionized water. The filtrate and the washings wascombined, cooled to a temperature of not higher than 10° C., and theprecipitated crystals were collected by filtration, washed with water,and dried to obtain(+)8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one·hydrochlorideas white crystals.

Yield=104.6 g. Percent yield=93%.

We claim:
 1. A process for producing a pyridoindole compound of theformula: ##STR6## where R¹ is hydrogen, a lower alkyl group or a loweralkenyl group, R² is hydrogen, a lower alkyl group or halogen, and R³ isan imidazolyl group optionally substituted by a lower alkyl moiety,or asalt thereof, by reacting a compound of the formula: ##STR7## where R¹and R² are respectively as indicated above, or a salt thereof with acompound of the formula: ##STR8## where R_(a) ³ is an imidazolyl groupsubstituted with an imino protective group, optionally substituted by alower alkyl moiety, and X is halogen,or a salt thereof and thensubjecting to a removal reaction of an imino protective group.
 2. Aprocess for producing a pyridoindole compound or a salt thereof of claim1, wherein R¹ is a lower alkyl group, R² is hydrogen, R³ is animidazolyl group substituted with a lower alkyl group, and R_(a) ³ is animidazolyl group substituted with an imino protective group, optionallysubstituted by a lower alkyl group.
 3. A process for producing anoptically active pyridoindole derivative of the formula: ##STR9## whereR¹ is hydrogen, a lower alkyl group or a lower alkenyl group, R² ishydrogen, a lower alkyl group or halogen, and R³ is an imidazolyl groupoptionally substituted by a lower alkyl moiety,or a salt thereof, byreacting a racemic mixture of a pyridoindole derivative of the formula:##STR10## where R¹, R², and R³ are respectively as indicated above, or asalt thereof with (1R)-(-)-10-camphorsulfonic acid.
 4. A process forproducing an optically active pyridoindole derivative or salt thereof ofclaim 3, wherein R¹ is a lower alkyl group, R² is hydrogen, and R³ is animidazolyl group optionally substituted by a lower alkyl.